Method of forming free flowing particles, containing a biologically valuable substance



24, 1965 A. B. GREVENSTUK ETAL 3,202,731

METHOD OF FORMING FREE FLOWING PARTICLES CONTAINING A, BIOLOGICALLYVALUABLE SUBSTANCE Filed April 5, 1961 INVENTOR FRANQOISJ.J.HOOGESTEGER.

ANTON B. GREVENSTUK.

BY [a i E 1 AG T United States Patent 0,

3,202,731 METHGD F FQG FREE FLOWING PARTI- CLES, CONTAINING ABIOLOGICALLY VALU- ABLE SUBSTANCE Anton Bernard Grevenstul; and FrancoisJohannes Jacobus Hoogesteger, both of Van Houtenlaan, Weesp,

Netherlands, assignors to North American Philips Company, Inc., NewYork, N.Y., a corporation of Delaware Filed Apr. 3, 1961, 'Ser. No.100,456 Claims priority, application Netherlands, Apr. 7, 1960,

250,281 12 Claims. (Cl. 264-7) This invention relates to a new and novelmethod of forming solid spherical particles from an aqueous emulsion orsolution, containing a biologically valuable substance and afilm-forming colloid and to a novel apparatus for use in such a method.

In the past attempts to form spherical particles from an aqueousemulsion 'or solution, containing abiologically valuable substance and afilm forming colloid have not been fully successful in that theparticles produced have been of irregular shapes or the processes havebeen unduly costly.

Thus according to one technique an emulsion which solidifies at roomtemperature and which contains a slowly solidifying substance isatomized into air at room temperature. However, such a technique has notproved a success because of the long time needed for the particles tosolidify.

In order to overcome this difliculty it has been proposed to atomizesuch an emulsion into a hot gas. However, this technique has thedrawbacks of requiring the use of an expensive drying tower and alsoresulting in porous, gas filled, irregularly shaped particles.

In another technique a vitamin emulsion is atomized into a cloud of awater absorbing powder such as starch or vegetable flour. This techniquehas the drawbacks of requiring regeneration of the water absorbingpowder after each operation and resulting in particles containing largeamounts of the water absorbing powder. In fact in one example of thistechnique such an emulsion is atomized into a vegetable flour which iskept into a fluidized state by an upwardly directed current of air. Inthis method no attempt is made to separate the flour from the solidifiedparticles.

Finally, in the so-called double emulsion technique a warm aqueousvitamin emulsion containing an'aqueous suspension of the vitamin in anaqueous solution of a film forming colloid is dispersed in a colderwater-insoluble oil and after the resultant solidification of thevitamin emulsion the oil is removed by washing with suitable solventsand then drying the resultant spherical particles. This method has thedisadvantages of being expensive and complicated due to the oil removingand drying steps and the need for regenerating the solvents and oilafter each operation. i

A principal object therefore of this invention is to provide .a lessexpensive and less complicated method of causing aqueous emulsion orsolutions, containing a biologically valuable substance and a filmforming colloid into spherical particles of uniform appearance.

Another object of this invention is to provide an apparatus particularlysuitable for carrying out the method of the invention. These and otherobjects of the inven tion will be apparent from the description thatfollows.

According to the invention the above-mentioned difliculties areeliminated bya new and novel method which comprises atomizing an aqueoussolution or emulsion capable of slow gelation, forcing the resultantdrops of said liquid to impinge upon a fluidized bed consisting3,Z@Z,73l Patented Aug. 24, 1965 initial-1y of a powdered lubricantsolid the particles of which are inert to said liquid and arenonabsorbent to said liquid and then of a mixture of said lubricant,solidified particles of said liquid and solidifying drops of said liquidsaid bed being kept at a temperature at which slow solidification ofsaid liquid drops takes place removing the resultant solid sphericalparticles of said drops from said fluidized bed and separating saidparticles from the lubricant.

The solid particles of the fluidized bed are preferably kept in thefluidized state by a current of gas directed upwardly through it.

The temperature of the fluidized bed is kept at one at which slowgelation of the liquid drops takes place. The exact temperature employeddepends in each instance upon the particular liquid to be solidified.Very good results are obtained by allowing liquid drops of a compositionthat is .a liquid at high temperature and which slowly solidifies atlower temperatures to impinge upon a fluidized bed held at a temperaturelow enough to cause solidification of said liquid.

As the lubricant powder a substance which is inert to the aqueoussolution or emulsion to be solidified, does not absorb any part of itand preferably which repells it should be employed. It is also importantthat the particle size of the lubricant powder be much smaller than thatof the particles of the solidified liquid in order not only to serve asa lubricant but also to be easily carried along by the gas currentdirected through the fluidized bed.

When solidifying water containing drops, metal salts of higher fattyacids for example magnesium, calcium or aluminum stearate or palmitatehave been formed to give good results. Especially good results haveresulted when calcium stearate having an average particle size of about5g is employed as the lubricant.

As the gas to be employed for fluidizing air at room temperature ispreferred although other inert gases which may also be kept cooler thenroom temperature may also be used.

The present invention is of particular importance for the method 'offorming a dry, free-flowing preparation stable in air, the separateparticles of which contain one or more biologically valuable substances,one or more antioxidants and/or synergists and in addition a filmformingcolloid and a carbohydrate, in which the substances of which theparticles are composed, are'dissolved or dispersed in warm water in aconcentration at which the warm mixture is fluid and slowly solidifiesat room temperature, which fluid is then atomised at a temperaturebetween 50 C. and C., and the resultant drops are forced to impinge upona fluidized bed according to the invention.

Examples of easily oxidisable, biologically valuable substance arevitamins, antibiotics, perfumes and proteins. Examples of such vitaminsare the vitamins A, D D and E. Examples of such antibiotics which are ofimportance are penicillin and tetracycline derivatives, inter aliaAureornycin and bacitracin.

In preparing the liquid composition the biologically valuable substancesmay be dissolved in the aqueous fluid. If, however, the fluids arenon-water-soluble but are oil-soluble, the aqueous liquid may containthe sub stance to be protected also in the form of a finely divided oilsolution. For example, oil-in-water emulsions are prepared of thefat-soluble vitamins A, D and E. If desired, the oil contains thevitamins A and/or D, partially in a microcrystalline state.

To the aqueous fluid there may be added one or more anti-oxidants,synergists or complex formers, for example butylated hydroxyphenols,such as 4-methyl 2,6-ditertiary butylphenol, 2-and 3-tertiarybutanol-4-hydroxyanisole nor-dihydroguaiaretic acid, alkyl gallates,such as the butyl, propyl, or octyl esters of gallic acid, ethylenediarnine tetraacetic acid or the alkali metal salts thereof, alsohydroguinone, vitamin C, citric acid, phosphoric acid, lecithin and thelike. However, the aqueous phase must contain one or more substanceswhich are capable of forming a solid protective coating enclosingbiologically valuable substance after solification of the drops formedwhen atomising. Said substances are used in a concentration at which thefluid solidifies at room temperature. These substances may comprises thesame mixtures of iium-forming colloids and carbohydrates which arecommonly used in the known technologies in this field for exampleproteins such as gelatin, albumin and casein, gums, for example gumarabic, cellulose ethers or esters and pectin or mixtures thereof, withcarbohydrates, for example glucose, saccharose, lactose, sorbitose andthe like.

Very favourable results are obtained, for example, if gelatin and pectinare used as the film-forming substances and the carbohydrates, such asglucose, saccharose and lactose are used together, preferably withgelatin, to fill the hollow structure of the resultant dried gelatedgelatin.

For atomising the fluid, various systems may be employed. In principlesit is possible to atomise the fluid on a rotating disc as a result ofwhich the fluid is scattered into very fine particles. The capacity ofthis type of atomiser as a rule is large, but a drawback is theformation of a spray cone having a large optical angle which wouldrequire a very wide fluid bed. Therefore a technique is required withwhich the fluid to be atomised is forced through a narrow aperture.

Very good results are obtained when using a two-phase atomiser in whicha comparatively large quantity of air or another gas together with thefluid to be atomised is passed under excess pressure through theatomiser. The specific atomiser specifications employed and the desiredparticle size of the final product determine the viscosity of the fluidto be atomised:

Thus to obtain a particle size of from 100-600 when using a two-phaseatomiser having a cross-section at the discharge aperture of from 1 to 5mms. at an atomising speed of 0.1-1 liter minute under an excesspressure of 0.2-1 atm. and with a gas excess pressure of 23.5atmospheres, the viscosity of the fluid should be between 100 and 600op. The viscosity required of an aqueous fluid containing a film-formingcolloid and other substances may be obtained either by choice of thetotal content of solid of the fluid mixture or by varying theconcentration of film-forming colloid at a given content of solid.

For example when using an aqueous fluid containing gelatin, acarbohydrate and a biologically valuable substance, it will bepreferable to obtain the highest possible content of solid because inthis case the highest possible production capacity of ultimate drypreparation i obtained at a given atomising speed. The solidificationtime of the particles depends strongly on the gelatin content, so thatthe content of solid at a required viscosity of the fluid to be atomisedis dependent upon this content.

The novel method of the invention has the advantages of producingspherical solid particles of substantially uniform size which do notadhere to the apparatus walls or to foreign substances. Because of theuniform size and shape of the particles produced the problems of qualitycontrol are eased and the miscibility with other substances such as foodis improved.

Also the cost of production is decreased because this novel methodparticularly lends itself to a continuous production. Further, since theonly other substance employed in the fluidized bed is a lubricant,expensive and complicated methods of separation are not required.

It is another important advantage of the method according to theinvention that very soft particles may be formed, so that a minimumquantity of gelatin is sufficient and the total content of solids of theliquids may be very high without the viscosity becoming too high foratomising.

For example, mixtures may be used consisting of 65- 45% of water and therest, i.e., the solid constituents inclusive of possible oilysubstances, of 10-65% of a filmforming colloid, for example gelatinand/or pectin, 8- 55% of one of more carbohydrates and 20-40% of abiologically valuable substance or a solution or dispersion thereof in awater immisicble fluid, for example oil. Good results were obtained inparticular when the aqueous fluid contains 6040% of water and the rest25-65% of gelatin, 2040% of carbohydrate and 2040% an oxidisablesubstance or solutions or dispersions thereof in oil. If a compositionof the emulsion is chosen so that the viscosity does not exceed 200 cp.at 70 C., particles of a particularly satisfactory spherical shape areobtained.

In order that the invention may be readily carried into effect it willnow be more specifically described by reference to the followingexamples and the accompanying drawing, FIGURE 1 of which is a crosssectional view of an apparatus suitable for use in the method of theinvention.

From the vessel 1 of FIGURE 1, the warm fluid is pumped to the atomiser3 via the surge vessel 2. At the same time, via the filter 4, compressedair or another inert gas under excess pressure is conducted to theatomiser. The atomiser is preferably provided in a vertical positioncentrally over the cylindrical chamber 5 which contains the fluid bed,in such a manner within a round aperture 6 in the cover 7 that duringatomising, gas which is outside the chamber 5 is sucked in or blown inalong the atomiser mouth. As a result of this any lubricant conductedalong with the fluidising gas current is prevented from reaching theatomiser aperture and being included in the still thin fluid drops.

The atomiser 3 is located at such a distance from the surface of thefluid bed 8 that the fluidising state in the upper layers of the fluidbed is not disturbed by the atomisation. In the case of a two-phaseatomiser as shown in FIGURE 1 for example the distance from the atomisermouth to the fluid bed surface preferably is not chosen smaller than 1.5m. if the diameter of the atomiser aperture is 1-5 mm. and -200 liter ofgas are blown through per minute. By this choice also the minimumcross-section of the chamber 5 is determined so that the number dropsatomised against the wall is kept at a mini mum. At a distance of 1.5 m.between the atomiser and the fluid bed surface, a chamber of a crosssection of at least 1.5 111. preferably employed.

The fluidised bed 8 consists of a mixture of lubricant alnd solidifyingand already solidified preparation partic es.

In order to obtain a uniform degree of fiuidisation throughout thefluidised bed it is preferable that there be a homogeneous distributionof the kinetic energy of the fluidising gas current before this currentreaches the powder mass. 7

In the device shown in FIGURE 1, this is achieved by providing a sievesystem between the gas supply chamber 9 and the powder mass, consistingof an upper layer which is formed by a textile fabric, for examplecotton cloth 10, and one or more lower layers 11 formed by a metal gauzehaving very fine apertures, for example electrolytic nickel gauze havingapertures of 4050,a diameter. Such a sieve system turned out to give notonly a very good distribution of the gas current, but in addition had alow resistance to the flow of this current.

When using such a device it was possible to maintain a very goodfluidisation state in a fluid bed having a crossscction of 1.5-2 m. anda height of from 20-30 ms.

It is of importance to keep the quantity of gas passing through as smallas possible so as to prevent atomisatiou of the lubricant. Therefore, astirrer 12 is preferably provided in the fluid bed, which stirrer isdriven by a motor 18 provided below the pressure chamber. When using astirrer, in which, as shown in the figure, horizontal blade-shapedarms13, are provided at an angle of for example 45 to the bottom of thesieve and the ends of Whichare provided with vertical blades 14 at anangle of approximately 45 to the sides of the wall, it is possible torestrict the gas current which is necessary for a good fiuidisationwithout the stirrer, to A of this flow rate- When using air asfluidising gas, a simple blower 15 may be used which drives the airthrough the mass at a linear speed of from 2-5 ems/sec; The air iscarried off through the apertures 7 in the top of the fluidisationchamber.

It is possible to perform the method according to the invention so thatthe fluidisation chamber contains lubricant only which is fluidisedafter which the preparation is atomised into it. It turned out that inthis case a minimum quantity of lubricant is necessary because at agiven mixing ratio of lubricant and preparation particles, preparationparticles are atomised in the bed after some time and no satisfactoryfluidisation condition can be maintained any longer. This minimumquantity of lubricant turned out to be for example ll5% by weight ofcalcium stearate of the total powder mass.

In a continuous method according to the invention, an amount of thesolidified preparation particles is conducted away via an exhaust 22equal to the amount of drops which is supplied to the bed by theatomizer. At the same time, the concentration of the lubricant in thebed is kept constant by continuously adding, via the aperture 19 and bymeans of a pump 21, as much lubricant from a storage vessel 22 as iswithdrawn with the preparation from the bed, via the exhaust 22. In sucha continuous method, the time required for a suflicient solidificationof the particles in the fluid bed can, in a simple manner,

be controlled by choice of the atomising rate. The solidifiedwatercontaining preparation particles mixed with lubricant, which leavethe fluid bed via the exhaust 22, are caught, for example, in a storagevessel and then dried batch-wise. For example, the particles are kept ina rotating drum for some hours at a temperature of from 30-65", whileair is blown through this drum with which the lubricant particles areconducted away and collected in a dust collecting devices.

In the following examples, specific forms of the use of the presentinvention are described for the production 'of dry and free-lowing,air-stable vitamin A preparations. In these examples the quantity ofthe'constitutents are always recited in parts by weight,

Example I 25 parts of gelatin and syrup containing 45 parts of glucosewere dissolved in a total amount 67 parts of water at70 C. 17 parts ofvitamin A-acetate heated at 70 C. were added to this solution as well asan antioxidant consisting of 13 parts of. ionol and 0.1 part of butylhydroxy anisol. The mixture was homogenised; The viscosity of theresulting emulsion was 120 cp.

The fluid was atomised through a so called 2-phase atomiser having anemulsion spray aperture of 2.8 mms. diameter. The quantity of fluidatomised per minute was from 500-600 ml. After a falling height of 1.70m., the

' drops were caught in a fluid bed which initially consisted ofair-fluidised calcium stearate. The final composition in the fluid bedwas: parts of vitamin A pills: 1 part of stearate. The resulting mixturewas transferred to a rotating drier in which, at an air temperature of40 C., drying and the separation of the vitamin A pills from thestearate was simultaneouslyperformed.

. Example 11 In the'manner as described in Example I, an emulsion wasprepared of the following composition:

127 parts of H 0 40 parts of gelatin 30 parts of glucose 23.3 parts ofvitamin A-palmitate 6.7 parts of 4-methyl 2,6-ditertiary butylphenolViscosity at 70 C.: cp.

This emulsion was atomised in a fluid bed withmagnesium stearate aslubricant, after which the solidified preparation was dried at 50 C. ina rotating drum in the same manner as in Example I. 1

Example III An emulsion of the composition:

60 parts of gelatin 7 10 parts of glucose g 16 parts of vitaminA-acetate 14 parts of ionol parts of water cle by means of a strongcurrent of air.

The preparations obtained according to the above described examplesconsisted of spherical pills having a diameter varying between 100 and6004p, substantially unmixed with smaller or larger particles. Thestearate content of the resultant pills was less than 5%.

, While We have described our invention in connection with specificembodiments and applications, other modifications thereof will .bereadily apparent to those skilled in this art Without departing from thespirit and scope of the invention as defined in the appended claims.

What is claimed is:

1. A method of manufacturing solid, air-stable free flowing, sphericalparticles each particle having a center portion containing anair-oxidizable substance and at least one antioxidant and an outerportion containing a film-forming colloid and a carbohydrate, saidmethod comprising the steps, forming in warm water an aqueous emulsionof said above-mentioned ingredients in a concentration such that saidmixture slowly hardens at room temperature, atomizing said aqueousemulsion at a temperature between about 50 C. and 100 C. into a gashaving a temperature low enough to cause the resultant fluid drops toslowly harden, forcing the resultant drops to impinge upon a fluidizedbed consisting initially of a non-water absorbent powdered lubricantsolid and then of a mixture of said solid lubricant powder, solidifiedspherical particles formed from said fluid drops and solidifying dropsformed from said fluid drops, said bed 7 kept in the fluidized state bymeans of an upwardly directed gas, said gas having a temperaturesufliciently low to cause the fluid drops to solidify, withdrawing theresultant solid spherical particles from the fluidized bed, removing thelubricant from said particles and drying said particles.

2. The method of claim 1 wherein the colloid is selected from the groupconsisting. of gelatin and pectin, glucose, dextrine and thecarbohydrate is selected from the group consisting of saccharose,lactose, glucose and dextrine.

3. The method of claim 1 wherein the atomized fluid consists of 65-45%by weight of Water and the remainder of which consists of 10-65% of afilm-forming colloid,

7 23-55% of at least one carbohydrate and -40% of a biologicallyvaluable substance.

4. The method of claim 3 wherein the fluid consists of -40% by weight ofwater and the remainder contains 25-65% of gelatin, 2040% of acarbohydrate and 20-40% of an oxidizable biologically valuable substancein an oil.

5. The method of claim 4, wherein the viscosity of the fluid to beatomised lies between 100 and 600 cp. at C.

6. The method of claim 4, wherein an emulsion is atomised having aviscosity between and 200 cp. at 70 C.

7. The method of claim 1 wherein a metal salt of a higher fatty acid isused as the lubricant.

8. The method of claim 1 wherein the lubricant is calcium stearatehaving an average particle diameter of approximately 5,14.

9. The method of claim 1 wherein solidified spherical particles formedfrom the slowly hardening composition is continuously withdrawn from thefluidized bed as the drops are continuously forced to impinge on :saidbed.

10. The method of claim 1 wherein the fluidisation of the'solids isobtained by means of a current of air at room temperature.

11. The method of claim 1 wherein the fluid bed the height is smallerthan the diameter of the surface.

8 12. The method of claim 9 wherein the fluidized bed contains from10%15% of calcium stearate.

References Cited by the Examiner 5 UNITED STATES PATENTS 2,217,711 10/40Shappirio. 2,411,897 12/46 Sahyun -65 2,561,395 7/51 Marshall 117-100 102,836,902 6/58 North 34-57 2,861,024 11/58 Silver 16782 2,887,724 5/59Bettes 264l4 2,987,444 6/ 61 Allardice 167--82 3,070,837 l/ 63Loertscher et al 264l4 15. FOREIGN PATENTS 161,054 2/55 Australia.708,160 4/54 Great Britain.

OTHER REFERENCES 20 American Pharmacy, edited by Lyman, J. B. LippincottCo., Philadelphia, 1947, pp. 219 and 220.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No\3,202,731 August 24, 1965 Anton Bernard Grevenstuk et alfl It is herebycertified that error appears in the above numbered patent requiringcorrection and that the said Letters Patent should read as correctedbelow.

Column 6, line 70, strike out "glucose, dextrine"; column 7, line 26,for "the fluid" read in the fluid "I Signed and sealed this 5th day ofJuly 19660 L) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A METHOD OF MANUFACTURING SOLID, AIR-STABLE FREE FLOWING, SPHERICALPARTICLES EACH PARTICLE HAVING A CENTER PORTION CONTAINING ANAIR-OXIDIZABLE SUBSTANCE AND AT LEAST ONE ANTIOXIDANT AND AN OUTERPORTION CONTAINING A FILM-FORMING COLLOID AND A CARBOHYDRATE, SAIDMETHOD COMPRISING THE STEPS, FORMING IN WARM WATER AN AQUEOUS EMULSIONOF SAID ABOVE-MENTIONED INGREDIENTS IN A CONCENTRATION SUCH THAT SAIDMIXTURE SLOWLY HARDENS AT ROOM TEMPERATURE, ATOMIZING SAID AQUEOUSEMULSION AT A TEMPERATURE BETWEEN ABOUT 50*C. AND 100*C. INTO A GASHAVING A TEMPERATURE LOW ENOUGH TO CAUSE THE RESULTANT FLUID DROPS TOSLOWLY HARDEN, FORCING THE RESULTANT DROPS TO IMPINGE UPON A FLUIDIZEDBED CONSISTING INITIALLY OF A NON-WATER ABSORBENT POWDERED LUBRICANTPOWDER, SOLIDIFIED SPHERICAL PARTICLES FORMED FROM SAID FLUID DROPS ANDSOLIDIFYING DROPS FORMED FROM SAID FLUID DROPS, SAID BED KEPT IN THEFLUIDIZED STATE BY MEANS OF AN UPWARDLY DIRECTED GAS, SAID GAS HAVING ATEMPERATURE SUFFICIENTLY LOW TO CAUSE THE FLUID DROPS TO SOLIDIFY,WITHDRAWING THE RESULTANT SOLID SPHERICAL PARTICALS FROM THE FLUIDIZEDBED, REMOVING THE LUBRICANT FROM SAID PARTICLES AND DRYING SAIDPARTICLES.